This invention relates to a novel and useful drug delivery device for releasing drug at a controlled rate for a prolonged period of time to produce a local or systemic physiological or pharmacological effect. The drug delivery device is comprised of a reservoir surrounded by a wall. The reservoir is comprised of a drug within a carrier permeable to the passage of the drug and in which the drug has limited solubility. The wall of the device is comprised in at least a part of a drug release rate controlling material permeable to the passage of the drug. Both the carrier and the wall are permeable to the passage of drug, as by diffusion, but the permeability of the wall to the drug is lower than the permeability of the carrier to the drug. Accordingly, drug release through the wall is the drug release rate controlling step for releasing drug from the drug delivery device of the invention.
the terms and phrases such as "reservoir", "carrier", "drug", "limited solubility", and the like that appear throughout the specification and the accompanying claims are defined in the specification in the section entitled, "Detailed Description of the Invention."
In many therapeutic programs pertaining to the management of health and disease, it is desirable and indicated to use a drug delivery device to provide for the slow release of a drug to the body at a controlled rate over a prolonged period of time to achieve a desired physiologic or pharmacologic effect. In many instances, such a rate of release of the drug from a drug delivery device should have a zero order time dependence, that is, the rate of drug release is independent of time.
Different approaches have been tried by the prior art to obtain such a drug delivery device. One approach, which has received great attention, is to mix a drug with a carrier material that is gradually broken down by body fluids with the drug released as the carrier disintegrates. Numerous carriers have been used in such devices including waxes, oils, fats, soluble polymers, and the like. While some of these devices have provided for a delayed release of the drug, the desired constant release rate for a prolonged period has not been obtained. One reason for this is that as the carrier disintegrates the surface area of the dosage unit decreases, concomitantly exposing increasingly smaller quantities of the carrier to the surrounding body fluids. This inherently results in a decline in the release rate over time.
Another approach to this problem has been to disperse the drug throughout a solid matrix material through which the desired amount of the drug is released by diffusion. But, this type of drug delivery device has proven incapable of providing a zero order drug release rate, because of the drawback that the release rate (dM.sub.t /dt) instead of being zero order (dM.sub.t /dt = constant) decreases with time (dM/dt = constant x t.sup..times..sup.-) during much of the drug release history; J. Pharm. Sci., Vol. 52, pages 1145 to 1149, 1963.
Still another approach has been to enclose the drug within a single capsule having a polymeric wall or walls through which the drug can pass, for example, by diffusion. An approach of this kind is set forth in U.S. Pat. No. 3,279,996. These devices too, have inherent difficulties. One difficulty encountered is that small devices containing a small amount of dry, powdered drug are hard to fabricate because the device can be manufactured from only a few materials and further because the materials having the drug must be non-toxic as they contact the body. Additionally, these prior art devices have generally been based on the use of a single material, such as silicone rubber polymers, especially polydimethylsiloxane, as the diffusion control membrane. In large part, these polymers were selected because of their permeability to some important drug molecules. But, it has been found that mere high permeability without consideration of release rate controlling properties can be a significant disadvantage which defeats the primary object of an acceptable drug delivery device. Thus, with many important drug molecules, such as progesterone, the diffusion rate through a polydimethylsiloxane membrane is very great, and it is often greater than the rate of clearance of the diffused drug from the outer surface of the capsule. In many instances this results in the rate limiting step being clearance of the drug from the exterior of the capsule, rather than diffusion through the capsule wall. Clearance rate within the body is difficult to control, as it is subject to frequent change, and this inherently defeats the objects of providing a drug delivery device which releases drug at a constant rate over prolonged time.
In my copending application, U.S. Ser. No. 42,786 filed June 2, 1970, and assigned to the assignee of this invention, there is described a drug delivery device comprised of a drug dispersed in a solid matrix permeable to passage of the drug and surrounded by a membrane, also permeable to passage of the drug but at a lower rate than through the matrix. That device has proven itself capable of zero order drug release and represents a substantial improvement over previously proposed drug delivery devices. However, in some instances, when zero order drug release is required for long periods of time, on the order of several months to a year or more, it may not be attained with the device of that copending patent application. Thus, it has been found that as drug is released by that device there is created over time a space in the solid matrix drug carrier which if not occupied by more drug can result in the carrier contracting and moving away from the membrane. The loss of contact between the carrier and the membrane at the carrier/membrane interface tends to decrease the availability of drug at the interface for release by the membrane. Thus, since the amount of drug available to the membrane is no longer constant, drug is released from the device at a continually reduced rate and the device does not maintain a constant zero order release rate. For applications in which controlled release is demanded for very long periods, this can be a problem.
It is also known to the art to incorporate drug into certain types of liquid carriers, usually in microcapsule formulations, for example. U.S. Pat. No. 3,464,413. However, these microcapsules are not designed for the controlled release of drug for a prolonged period of time by using drug release rate controlling materials. The mirocapsules are frequently crushable, and they merely function as drug carriers supplying their drug in bulk, and not in controlled amounts by rupture of the microcapsules. Therefore, these types of capsules are not suitable for releasing drug at a controlled rate for a prolonged peroid of time.